The Wheeling Symphony Orchestra, one of West Virginia's major cultural institutions, had its beginnings in a fall 1928 meeting at the home of Eleanor Caldwell. Under the leadership of Caldwell and with the support of local citizens, the Wheeling Symphony soon became a reality, appearing in its first concert on Sunday, June 30, 1929, at Oglebay Park. Under the direction of Enrico Tamburini, the new orchestra performed Mozart's Overture to Don Juan and Schubert's Unfinished Symphony, among other works.

Tamburini, the first conductor, helped to mold the fledgling group of amateurs and professionals into a cohesive ensemble. When he left in 1934, Antonio Modarelli took over, coming from the Pittsburgh Symphony. The ascension in 1947 of the able and charismatic Henry Mazer signaled a new era of professionalism for the Wheeling Symphony. Mazer had been an assistant to the outstanding conductor Fritz Reiner, at Chicago, and at Wheeling he developed an expanded program of opera, choral works, and chamber music, and performances by distinguished guest artists, such as Yehudi Menuhin, Benny Goodman, and Artur Rubinstein.

With Mazer's departure in 1960, Henry Aaron, William Steinberg's assistant in Buffalo, was appointed. He left Wheeling in 1964, and once again the symphony hired an assistant conductor of the Pittsburgh Symphony, Robert Kreis. He was a classicist, filling the winter season with traditional favorites and the summer program with popular music and show tunes. He instituted the symphony's first concert tours in 1971.

When Kreis left in 1972, a year of guest conductors followed, from whom was selected Jeff Holland Cook to be Wheeling Symphony's sixth music director, beginning with the 1973—74 season. As a former professional trombonist and conductor of the Rhode Island Philharmonic Orchestra, Cook brought extensive training and experience. He continued the effort to bring in outstanding guest artists, including Arthur Fiedler, Doc Severinsen, Itzhak Perlman, and Eleanor Steber, Wheeling's own opera diva, among others.

Rachael Worby became music director in 1986 and continued to expand on a vital tradition, increasing the number of performances each year from six to 40. She created a pops series, presented guest artists such as Eugenia Zukerman and Jean-Pierre Rampal, and led a successful touring program. Worby left in 2003, to be succeeded by Andre Raphel.

The regular performance home of the symphony is Capitol Music Hall in downtown Wheeling.